CN113979850A - 一种二萜衍生物及其制备方法、药物组合物和应用 - Google Patents

一种二萜衍生物及其制备方法、药物组合物和应用 Download PDF

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CN113979850A
CN113979850A CN202111315072.1A CN202111315072A CN113979850A CN 113979850 A CN113979850 A CN 113979850A CN 202111315072 A CN202111315072 A CN 202111315072A CN 113979850 A CN113979850 A CN 113979850A
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杨诚
曹胜
王宁
张坤
杨光
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Nankai University
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Abstract

本发明公开了一种二萜衍生物及其制备方法、药物组合物和应用，该二萜衍生物结构如式Ⅰ所示，R1为苯基、链状脂肪烃、环状脂肪烃或含杂原子芳香环。本发明获得了一种新型二萜衍生物，制备过程简便易行，对多种肿瘤细胞增殖均有一定抑制作用，适合用于抗肿瘤药物的开发。

Description

一种二萜衍生物及其制备方法、药物组合物和应用
技术领域
本发明属于化药领域，具体涉及一种二萜衍生物及其制备方法、药物组合物和应用。
背景技术
肿瘤是指机体在各种致瘤因子作用下，局部组织细胞增生所形成的新生物。肿瘤尤其是恶性肿瘤是当前威胁人类生命健康的一种最主要因素，据世界卫生组织最新统计结果显示，2 020年约有1000万人死于恶性肿瘤，成为全球致死率最高的疾病之一2020年全球新发恶性肿瘤1930万例，预计2040年将增至2840万例，较2020年增加47％，其中，中等和低等人口发展指数国家的病例数增幅尤为显著，可分别达到95％和64％。当前，治疗肿瘤的方法主要有手术治疗，放射治疗和药物治疗等方法。肿瘤的药物治疗包含化学药物、基因药物以及肿瘤的靶向治疗和免疫治疗。化学药物的开发仍是当前抗肿瘤药物研发的重要方向。
化疗是化学药物治疗的简称，化学药物治疗的作用是阻止或缓解肿瘤细胞的增长。化疗药物价格相对低廉，在多数肿瘤治疗领域仍处于一线治疗地位，此外由于无需进行药物敏感性标志物的检测，适应人群更广，临床应用也更便利，是肿瘤治疗方法中不可或缺的组成部分，也是目前治疗肿瘤的最有效手段之一。传统化疗药物通常分为烷化剂、抗生素类、和抗代谢类等，主要通过干扰RNA或DNA合成以及有丝分裂等，抑制快速生长的细胞。如：干扰细胞有丝分裂的紫杉醇是20世纪下半叶举世瞩目的抗肿瘤明星化疗药物，广泛用于乳腺癌、卵巢癌和肺癌的治疗；由赛诺菲研发的作用于DNA的奥沙利铂，临床用于结肠癌和卵巢癌的治疗，销售额在2011年达到10亿欧元；抗代谢类抗肿瘤药物吉西他滨已在90多个国家获得批准使用，是非小细胞肺癌的一线药物和治疗胰腺癌的“金标准”。虽然化疗药物大大提高了恶性肿瘤的治疗效果，并有效地控制了癌肿的扩散和转移，但可选择的化疗药物非常有限，同时也会出现恶心、呕吐、脱发等副作用。为拓展可选择的化疗药物的种类，同时降低治疗过程中所产生的毒副作用。因此开发高效、低毒的化疗药物具有重要意义。
发明内容
为解决前述问题，本发明提供了一种二萜衍生物，含有作为活性成分的二萜衍生物的治疗癌症药物组合物，以及制备新型二萜衍生物的方法。
为了实现本发明的上述目的，本发明提供如下的技术方案：
一种二萜衍生物，其结构如式Ⅰ所示：
Figure BDA0003343357760000021
式Ⅰ，
所述R1为苯基、链状脂肪烃、环状脂肪烃或含杂原子芳香环。
优选的，R1的结构为化合物3-27中的一种：
Figure BDA0003343357760000022
Figure BDA0003343357760000031
本发明还提供了上述二萜衍生物的制备方法，其制备路线如下所示：
Figure BDA0003343357760000032
经过发明人研究发现，上述二萜衍生物能够应用在制备治疗癌症、预防癌症和/或改善癌症症状的药物或食品中。可作为治疗癌症的药物组合物的活性成分，该要用组合物还包括溶剂或可药用载体。
上述癌症包括：妇科癌类，例如：卵巢癌、子宫颈癌、阴道癌、阴部癌、子宫/子宫内膜癌、妊娠滋养细胞肿瘤、输卵管癌、子宫肉瘤；内分泌癌类，例如：肾上腺皮质癌、脑垂体癌、胰癌、甲状腺癌、副甲状腺癌、胸腺癌、多发性内分泌肿瘤；骨癌类，例如：骨肉瘤、尤因肉瘤、软骨肉瘤等；肺癌类，例如：小细胞肺癌、非小细胞肺癌；脑和CNS肿瘤，例如：神经母细胞瘤、听神经瘤、神经胶瘤和其他脑肿瘤，脊髓肿瘤、乳癌、结肠直肠癌、晚期结肠直肠腺癌；胃肠癌类，例如：肝癌、肝外胆管癌、胃肠类癌性肿瘤、胆囊癌、胃癌、食道癌、小肠癌；泌尿生殖器癌类，例如：阴茎癌、翠丸癌、前列腺癌；头和颈部肿瘤类，例如：鼻癌、鼻窦癌、鼻咽癌、口腔癌、唇癌、唾腺癌、喉头癌、下咽癌、正咽癌；血癌类，例如：急性骨髓性白血病、急性淋巴性白血病、儿童白血病、慢性淋巴性白血病、慢性骨髓性白血病、发状细胞性白血病、急性早幼粒细胞白血病、血浆细胞性白血病；骨髓癌血液病症，例如：骨髓分化不良症候群、骨髓增生性病症、范禾尼贫血、再生障碍性贫血、特发性巨球蛋白血症；淋巴癌类，例如：霍奇金病、非霍奇金氏淋巴瘤、周围T-细胞林巴瘤、皮肤型T-细胞淋巴瘤、AIDS相关性淋巴瘤；眼癌类，包括：视网膜母细胞瘤、葡萄膜黑色素瘤；皮肤癌类，例如：黑色素瘤、非黑色素瘤皮肤癌、梅克尔细胞癌；软组织肉瘤类，例如：卡波希肉瘤、儿童软组织肉瘤、成人软组织肉瘤、泌尿系统癌症，例如：肾癌维尔姆斯肿瘤、膀肤癌、尿道癌和转移性细胞癌。优选用于乳腺癌、结直肠癌、肺癌的治疗。
本发明的有益效果为：本发明获得了一种新型二萜衍生物，制备过程简便易行，对多种肿瘤细胞增殖均有一定抑制作用，适合用于抗肿瘤药物的开发。
具体实施方式
除有定义外，以下实施例中所用的技术术语具有与本发明创造所属领域技术人员普遍理解的相同含义。以下实施例中所用的试验试剂，如无特殊说明，均为常规生化试剂；所述实验方法，如无特殊说明，均为常规方法。
下面结合实施例来详细说明本发明创造。
实施例1：二萜衍生物的制备
(1)化合物3的制备：
化合物3的结构如下：
Figure BDA0003343357760000041
其制备过程如下：
在室温下，向截短侧耳素(化合物1，7.00g，22.1毫摩尔)的乙醇(50毫升)和水(32毫升) 的溶液中加入50％氢氧化钠水溶液(3.70毫升)。在65℃搅拌1小时后，将反应混合物冷却至室温并过滤，滤液用1N盐酸酸化至pH＝2，然后用乙酸乙酯(200毫升)稀释；分离有机相，水相用乙酸乙酯(3×200毫升)萃取；合并的有机相用饱和食盐水洗涤，用无水硫酸钠干燥，真空浓缩，直接用于下一步作为化合物2。
将化合物2(200毫克，0.63毫摩尔)溶于EtOH(4毫升)，溶液为无色透明状液体。加入KOH(247.4毫克，4.41毫摩尔)，搅拌至完全溶解，溶液为淡黄色液体。加入苯甲醛(7 3.5毫克，0.693毫摩尔)，加热回流，搅拌3h后，化合物2反应完全。真空浓缩除去EtOH，用1NHCl调节反应体系pH至2-3；分离有机相，水相用乙酸乙酯(3×20毫升)萃取；合并的有机相用无水硫酸钠干燥，真空浓缩，得到粗产物；然后通过硅胶快速柱色谱(石油醚：乙酸乙酯＝12：1)，得到化合物3(173.4毫克，68％，白色固体)。
对化合物3进行检测，其检测结果如下：1H NMR(400MHz,CDCl3)δ7.51(d,J＝1.7Hz,1H),7.49(s,1H),7.43(q,J＝2.1,1.5Hz,1H),7.40(d,J＝2.1Hz,1H),7.38(d,J＝6.4Hz,1H),7.34(d,J＝7.3Hz,1H),6.19(dd,J＝17.8,11.1Hz,1H),5.40(dd,J＝17.8,1.4Hz,1H),5.32(dd,J＝11.1,1.4Hz,1H),4.43(dd,J＝7.6,4.8Hz,1H),3.51(t,J＝6.1Hz,1H),2.58(dd,J＝16.9,3.3Hz,1H),2.46(dd,J＝16.8,2.1Hz,1H),2.31–2.22(m,2H),1.9 9(dd,J＝15.8,7.7Hz,1H),1.78–1.74(m,1H),1.72(q,J＝2.7Hz,1H),1.59(d,J＝4.6Hz,2H),1.49(s,3H),1.38(q,J＝3.7Hz,1H),1.31(d,J＝5.5Hz,1H),1.25(d,J＝2.2Hz,1 H),1.17(s,3H),1.03(s,2H),1.01(d,J＝2.4Hz,3H),0.99(s,2H).13C NMR(100MHz, CDCl3)δ206.2,139.5,135.7,135.2,133.3,130.4,129.3,128.8,116.2,75.4,66.9,59.3,4 5.5,45.2,44.0,42.9,37.0,36.3,35.3,32.1,28.6,27.3,18.3,13.8,11.8.HRMS(ESI):m/zcalcd for C27H36NaO3 +[M+Na]+:431.2562；found 431.2563。
(2)化合物4的制备：
化合物4的结构如下：
Figure BDA0003343357760000051
其制备过程如下：
使用2-萘甲醛(108.2毫克，0.693毫摩尔)，按照化合物3所述的合成步骤获得目标化合物4。快速柱色谱(石油醚：乙酸乙酯＝12：1)得到化合物4(183.3毫克，64％，白色固体)。
对化合物4进行检测，其检测结果如下：1H NMR(400MHz,CDCl3)δ7.96(s,1H),7.85(q,J＝7.7,4.9Hz,3H),7.61(d,J＝9.5Hz,2H),7.55–7.47(m,2H),6.21(dd,J＝17.8,11.1Hz,1H),5.37(dd,J＝30.9,14.4Hz,2H),4.44(d,J＝5.8Hz,1H),3.55(d,J＝6.6Hz,1H),2.69(d,J＝16.9Hz,1H),2.57(d,J＝16.8Hz,1H),2.34–2.23(m,2H),2.01(dd,J＝16.0,7.6Hz,1H),1.76(d,J＝13.9Hz,2H),1.65(d,J＝16.9Hz,2H),1.60(s,2H),1.53–1.49(m,3H),1.32(d,J＝5.2Hz,1H),1.27(d,J＝11.2Hz,1H),1.18(s,3H),1.05(d,J＝7.0H z,3H),1.01(d,J＝7.1Hz,3H).13C NMR(100MHz,CDCl3)δ206.1,139.5,135.4,133.5, 133.5,133.4,133.3,130.8,128.6,128.5,127.8,127.2,127.0,126.7,116.3,75.4,67.0,59. 3,45.6,45.3,44.1,43.0,37.1,36.4,35.4,32.2,28.6,27.3,18.3,13.8,11.9.HRMS(ESI):m/z calcd for C31H38NaO3 +[M+Na]+:481.2719；found 481.2722。
(3)化合物5的制备：
化合物5的结构如下：
Figure BDA0003343357760000061
其制备过程如下：
使用3-甲基苯甲醛(83.3毫克，0.693毫摩尔)，按照化合物3所述的合成步骤获得目标化合物5。快速柱色谱(石油醚：乙酸乙酯＝12：1)得到化合物5(174.2毫克，66％，白色固体)。
对化合物5进行检测，其检测结果如下：1H NMR(400MHz,CDCl3)δ7.41(t,J＝2.6Hz,1H),7.30(d,J＝6.9Hz,3H),7.20–7.15(m,1H),6.19(dd,J＝17.8,11.1Hz,1H),5.40(dd,J＝17.9,1.4Hz,1H),5.32(dd,J＝11.1,1.3Hz,1H),4.43(d,J＝7.5Hz,1H),3.51(s,1H),2.57(dd,J＝16.9,3.2Hz,1H),2.46(dd,J＝16.8,2.0Hz,1H),2.38(s,3H),2.30–2.23(m,2H),1.99(dd,J＝15.8,7.7Hz,1H),1.73(dq,J＝16.5,5.1,4.2Hz,2H),1.66–1.56(m,3H),1.49(s,3H),1.39–1.29(m,2H),1.17(s,3H),1.09(dd,J＝14.2,4.5Hz,1H),1.02 (d,J＝7.5Hz,3H),0.99(d,J＝7.3Hz,3H).13C NMR(100MHz,CDCl3)δ206.2,139.5,1 38.5,135.7,135.0,133.5,131.3,130.2,128.7,127.3,116.2,75.4,66.9,59.3,45.6,45.2,44.0,42.9,37.0,36.3,35.3,32.1,28.6,27.3,21.6,18.3,13.8,11.8.HRMS(ESI):m/zcalcd for C28H38NaO3 +[M+Na]+:445.2719；found 445.2720。
(4)化合物6的制备：
化合物6的结构如下：
Figure BDA0003343357760000062
其制备过程如下：
使用4-甲基苯甲醛(83.3毫克，0.693毫摩尔)，按照化合物3所述的合成步骤获得目标化合物6。快速柱色谱(石油醚：乙酸乙酯＝12：1)得到化合物6(179.5毫克，68％，白色固体)。
对化合物6进行检测，其检测结果如下：1H NMR(400MHz,CDCl3)δ7.40(d,J＝8.1Hz,3H),7.21(d,J＝7.9Hz,2H),6.19(dd,J＝17.8,11.1Hz,1H),5.44–5.28(m,2H),4.4 3(dd,J＝7.6,4.7Hz,1H),3.51(t,J＝6.2Hz,1H),2.56(dd,J＝16.7,3.1Hz,1H),2.44(dd, J＝16.9,2.0Hz,1H),2.38(s,3H),2.32–2.19(m,2H),1.99(dd,J＝15.9,7.7Hz,1H),1.78 –1.70(m,2H),1.64–1.55(m,3H),1.49(s,3H),1.40–1.29(m,2H),1.17(s,3H),1.10(dd, J＝14.7,3.4Hz,1H),1.01(dd,J＝9.9,7.2Hz,6H).13C NMR(100MHz,CDCl3)δ206.2, 139.7,139.5,134.2,133.3,132.9,130.4,129.6,116.2,75.4,67.0,59.3,45.6,45.3,44.0,42.9,37.0,36.4,35.4,32.1,28.6,27.4,21.6,18.3,13.8,11.8.HRMS(ESI):m/z calcd forC28H38NaO3 +[M+Na]+:445.2719；found 445.2721。
(5)化合物7的制备：
化合物7的结构如下：
Figure BDA0003343357760000071
其制备过程如下：
使用2-甲基苯甲醛(83.3毫克，0.693毫摩尔)，按照化合物3所述的合成步骤获得目标化合物7。快速柱色谱(石油醚：乙酸乙酯＝12：1)得到化合物7(176.8毫克，67％，白色固体)。
对化合物7进行检测，其检测结果如下：1H NMR(400MHz,CDCl3)δ7.68(dd,J＝3.3,1.9 Hz,1H),7.43–7.38(m,1H),7.25–7.20(m,3H),6.18(dd,J＝17.8,11.1Hz,1H),5.39(dd,J＝17.8, 1.4Hz,1H),5.32(dd,J＝11.1,1.4Hz,1H),4.43(d,J＝7.6Hz,1H),3.51(d,J＝6.4Hz,1H),2.53(dd, J＝16.7,3.3Hz,1H),2.40(s,3H),2.29(d,J＝3.0Hz,1H),2.24(d,J＝6.9Hz,1H),2.06–2.00(m,1H), 1.98(d,J＝7.7Hz,1H),1.76–1.67(m,3H),1.66(s,1H),1.62(s,1H),1.50(s,3H),1.38(q,J＝3.7 Hz,1H),1.27–1.22(m,1H),1.18(s,3H),1.11–1.05(m,1H),1.00(d,J＝7.1Hz,3H),0.97(d,J＝7.1 Hz,3H).13C NMR(100MHz,CDCl3)δ206.1,139.4,138.8,135.6,134.3,130.9,130.6,129.1, 128.4,125.9,116.1,75.2,66.8,59.4,45.5,45.1,43.9,42.9,37.0,36.2,34.9,31.7,28.5,27.2,20.0, 18.17,13.7,11.7.HRMS(ESI):m/z calcd for C28H38NaO3 +[M+Na]+:445.2719；found 445.2721。
(6)化合物8的制备：
化合物8的结构如下：
Figure BDA0003343357760000072
其制备过程如下：
使用4-叔丁基苯甲醛(112.4毫克，0.693毫摩尔)，按照化合物3所述的合成步骤获得目标化合物8。快速柱色谱(石油醚：乙酸乙酯＝12：1)得到化合物8(194.4毫克，67％，白色固体)。
对化合物8进行检测，其检测结果如下：1H NMR(400MHz,CDCl3)δ7.46(d,J＝8.7Hz, 2H),7.43(d,J＝6.2Hz,3H),6.19(dd,J＝17.7,11.1Hz,1H),5.40(dd,J＝17.8,1.4Hz,1H),5.32(dd, J＝11.1,1.4Hz,1H),4.42(dd,J＝7.5,5.3Hz,1H),3.51(t,J＝6.4Hz,1H),2.56(dd,J＝16.8,3.2Hz, 1H),2.46(dd,J＝16.8,2.0Hz,1H),2.29–2.21(m,2H),1.99(dd,J＝15.8,7.6Hz,1H),1.78–1.68(m, 3H),1.62(dd,J＝15.3,8.2Hz,3H),1.49(s,3H),1.38–1.35(m,1H),1.33(s,9H),1.17(s,3H), 1.12–1.06(m,1H),1.02(d,J＝7.0Hz,3H),0.99(d,J＝7.1Hz,3H).13C NMR(100MHz,CDCl3)δ 206.3,152.8,139.5,134.4,133.2,132.9,130.3,125.8,116.2,75.3,66.9,59.3,45.5,45.2,44.0,42.9, 37.0,36.3,35.3,35.0,32.1,31.3,28.6,27.3,18.3,13.8,11.8.HRMS(ESI):m/z calcd for C31H44NaO3 +[M+Na]+:487.3188；found 487.3187。
(7)化合物9的制备：
化合物9的结构如下：
Figure BDA0003343357760000081
其制备过程如下：
使用2,4,6-三甲基苯甲醛(102.7毫克，0.693毫摩尔)，按照化合物3所述的合成步骤获得目标化合物9。快速柱色谱(石油醚：乙酸乙酯＝12：1)得到化合物9(188.6毫克，67％，白色固体)。
对化合物9进行检测，其检测结果如下：1H NMR(400MHz,CDCl3)δ7.51(d,J＝2.9Hz,1H),6.87(s,2H),6.15(dd,J＝17.8,11.1Hz,1H),5.45–5.23(m,2H),4.40(d,J＝7.5Hz,1H),3.41(d,J＝6.3Hz,1H),2.29(d,J＝9.0Hz,3H),2.29–2.23(m,1H),2.19(q,J ＝6.9Hz,2H),2.13(s,4H),2.08–1.94(m,2H),1.83(dd,J＝16.5,2.0Hz,1H),1.75–1.66 (m,2H),1.63(d,J＝15.8Hz,1H),1.60–1.52(m,1H),1.50(s,3H),1.49–1.42(m,1H),1.4 1–1.33(m,2H),1.32–1.22(m,1H),1.15(d,J＝4.2Hz,3H),1.09(dd,J＝13.9,4.5Hz,1H),1.00(d,J＝7.0Hz,3H),0.83(d,J＝7.1Hz,3H).13C NMR(100MHz,CDCl3)δ205.4,1 39.4,138.4,137.3,135.5,133.5,132.0,128.2,116.0,75.1,66.8,59.7,45.4,45.1,43.4,43.0,37.2,36.2,33.7,31.6,28.6,27.1,21.0,20.3,18.2,13.7,11.6.HRMS(ESI):m/z calcdf or C30H42NaO3 +[M+Na]+:473.3032；found 473.3033。
(8)化合物10的制备：
化合物10的结构如下：
Figure BDA0003343357760000091
其制备过程如下：
使用4-甲氧基苯甲醛(94.4毫克，0.693毫摩尔)，按照化合物3所述的步骤获得目标化合物10。快速柱色谱(石油醚：乙酸乙酯＝12：1)得到化合物10(189.0毫克，69％，白色固体)。
对化合物10进行检测，其检测结果如下：1H NMR(400MHz,CDCl3)δ7.46(d,J＝8.8Hz, 2H),7.39(d,J＝2.7Hz,1H),6.94–6.90(m,2H),6.19(dd,J＝17.8,11.1Hz,1H),5.39(dd,J＝17.8, 1.4Hz,1H),5.31(dd,J＝11.2,1.4Hz,1H),4.42(d,J＝7.5Hz,1H),3.83(s,3H),3.50(d,J＝6.3Hz, 1H),2.53(dd,J＝16.7,3.2Hz,1H),2.41(dd,J＝16.7,2.0Hz,1H),2.25(q,J＝6.7,5.7Hz,2H),1.98 (dd,J＝15.8,7.7Hz,1H),1.75–1.69(m,2H),1.63(d,J＝15.9Hz,2H),1.48(s,3H),1.35(dq,J＝14.1, 3.6Hz,2H),1.16(s,3H),1.09(ddd,J＝13.8,9.6,3.3Hz,2H),1.02(d,J＝7.1Hz,3H),0.99(d,J＝7.1 Hz,3H).13C NMR(100MHz,CDCl3)δ206.2,160.4,139.4,133.0,132.7,132.0,128.3,116.1, 114.2,75.2,66.8,59.0,55.4,45.4,45.1,43.9,42.8,36.9,36.2,35.2,32.0,28.5,27.2,18.2,13.7, 11.7.HRMS(ESI):m/z calcd for C28H38NaO4 +[M+Na]+:461.2668；found 461.2667。
(9)化合物11的制备：
化合物11的结构如下：
Figure BDA0003343357760000092
其制备过程如下：
使用4-(甲基巯基)苯甲醛(105.5毫克，0.693毫摩尔)，按照化合物3所述的步骤获得目标化合物11。快速柱色谱(石油醚：乙酸乙酯＝12：1)得到化合物11(195.9毫克，69％，白色固体)。
对化合物11进行检测，其检测结果如下：1H NMR(400MHz,CDCl3)δ7.28(s,1H),7.24 (d,J＝2.7Hz,1H),7.12(s,1H),7.09(d,J＝8.2Hz,2H),6.04(dd,J＝17.8,11.1Hz,1H),5.25(dd, J＝17.7,1.4Hz,1H),5.17(dd,J＝11.1,1.3Hz,1H),4.28(t,J＝6.3Hz,1H),3.35(t,J＝6.4Hz,1H), 2.36(s,3H),2.11(t,J＝5.6Hz,2H),1.83(dd,J＝15.8,7.7Hz,1H),1.63–1.55(m,2H),1.52–1.45(m, 2H),1.34(s,3H),1.30(d,J＝8.8Hz,1H),1.23(d,J＝3.3Hz,1H),1.20(d,J＝5.3Hz,2H),1.15–1.08 (m,1H),1.02(s,3H),0.95(d,J＝15.3Hz,1H),0.88(s,2H),0.86(d,J＝3.4Hz,3H),0.84(s, 1H).13C NMR(100MHz,CDCl3)δ206.2,140.8,139.5,134.3,132.7,132.1,130.7,126.0,116.2, 75.3,66.9,59.2,45.5,45.2,44.0,42.9,37.0,36.3,35.4,32.1,28.6,27.3,18.3,15.3,13.8,11.8. HRMS(ESI):m/zcalcd for C28H38NaO3S+[M+Na]+:477.2439；found 477.2440。
(10)化合物12的制备：
化合物12的结构如下：
Figure BDA0003343357760000101
其制备过程如下：
使用4-氯苯甲醛(97.4毫克，0.693毫摩尔)，按照化合物3所述的步骤获得目标化合物1 2。快速柱色谱(石油醚：乙酸乙酯＝12：1)得到化合物12(196.4毫克，71％，白色固体)。
对化合物12进行检测，其检测结果如下：1H NMR(400MHz,CDCl3)δ7.41(d,J＝8.5Hz, 2H),7.36(s,2H),7.34(s,1H),6.18(dd,J＝17.8,11.1Hz,1H),5.39(dd,J＝17.8,1.4Hz,1H),5.31 (dd,J＝11.0,1.4Hz,1H),4.41(d,J＝7.5Hz,1H),3.48(s,1H),2.53(dd,J＝16.9,3.3Hz,1H),2.40 (dd,J＝16.9,2.1Hz,1H),2.30–2.21(m,2H),1.97(dd,J＝15.9,7.7Hz,1H),1.74(dq,J＝15.9,4.4, 3.5Hz,2H),1.63(d,J＝15.9Hz,2H),1.59–1.49(m,1H),1.47(s,3H),1.40–1.31(m,2H),1.16(s, 3H),1.06(dd,J＝14.1,4.5Hz,1H),1.00(dd,J＝9.2,7.1Hz,3H),δ0.99(d,J＝7.1Hz,3H).13C NMR(100MHz,CDCl3)δ205.9,139.3,135.6,135.1,134.0,131.8,131.4,129.0,116.2,75.2,66.8, 59.3,45.4,45.1,43.9,42.8,36.9,36.2,35.1,32.1,28.5,27.2,18.2,13.7,11.7.HRMS(ESI):m/z calcd forC27H35ClNaO3 +[M+Na]+:465.2172；found 465.2173。
(11)化合物13的制备：
化合物13的结构如下：
Figure BDA0003343357760000102
其制备过程如下：
使用4-氟苯甲醛(86.0毫克，0.693毫摩尔)，按照化合物3所述的合成步骤得到化合物1 3。快速柱色谱(聚乙烯：乙酸乙酯＝12：1)得到13(186.5毫克，70％，白色固体)。
对化合物13进行检测，其检测结果如下：1H NMR(400MHz,CDCl3)δ7.41(dd,J＝8.6,5.6 Hz,2H),7.32(s,1H),7.02(t,J＝8.6Hz,2H),6.12(dd,J＝17.8,11.1Hz,1H),5.36–5.21(m,2H), 4.40–4.30(m,1H),3.43(t,J＝6.6Hz,1H),2.47(dd,J＝16.8,3.2Hz,1H),2.34(dd,J＝16.8,2.1Hz, 1H),2.22–2.15(m,2H),1.91(dd,J＝15.9,7.7Hz,1H),1.71–1.62(m,2H),1.59(s,1H),1.54(d, J＝8.9Hz,1H),1.42(s,3H),1.29(dd,J＝15.8,4.6Hz,2H),1.10(s,3H),1.06–0.99(m,1H),0.95(d, J＝7.1Hz,3H),0.93(d,J＝7.0Hz,3H).13C NMR(100MHz,CDCl3)δ205.9,164.3,161.8,139.3, 134.6,132.1(d,JF-C＝8.7Hz),132.0,116.1(d,JF-C＝19.5Hz),115.8,75.23,66.8,59.2,45.4,45.1, 43.9,42.8,36.9,36.2,35.1,32.1,28.5,27.2,18.2,13.7,11.7.HRMS(ESI):m/z calcd forC27H35FNaO3 +[M+Na]+:449.2468；found 449.2465。
(12)化合物14的制备：
化合物14的结构如下：
Figure BDA0003343357760000111
其制备过程如下：
使用4-三氟甲基苯甲醛(120.7毫克，0.693毫摩尔)，按照化合物3所述的合成步骤获得目标化合物14。快速柱色谱(石油醚：乙酸乙酯＝12：1)得到化合物14(205.4毫克，69％，白色固体)。
对化合物14进行检测，其检测结果如下：1H NMR(400MHz,CDCl3)δ7.65(d,J＝8.2Hz, 2H),7.58(d,J＝8.2Hz,2H),7.43(d,J＝2.5Hz,1H),6.18(dd,J＝17.8,11.1Hz,1H),5.40(d,J＝17.7 Hz,1H),5.33(d,J＝11.1Hz,1H),4.43(d,J＝7.6Hz,1H),3.49(d,J＝6.2Hz,1H),2.59(dd,J＝17.1, 3.3Hz,1H),2.44(dd,J＝17.0,2.0Hz,1H),2.29(d,J＝2.9Hz,1H),2.02–1.93(m,1H),1.82–1.69 (m,2H),1.67(s,1H),1.63(s,2H),1.49(s,3H),1.44–1.38(m,1H),1.33(s,1H),1.27(d,J＝11.3Hz, 2H),1.17(s,3H),1.01(t,J＝6.8Hz,6H).13C NMR(100MHz,CDCl3)δ205.8,139.3,139.1,137.6, 131.4,130.9,130.6,130.3,125.7(q,J＝3.8Hz),116.4,75.4,66.9,59.5,45.6,45.2,44.1,43.0,37.0, 36.3,35.3,32.2,28.6,27.3,18.3,13.8,11.8.HRMS(ESI):m/z calcd for C28H35F3NaO3 + [M+Na]+:499.2436；found 499.2437。
(13)化合物15的制备：
化合物15的结构如下：
Figure BDA0003343357760000121
其制备过程如下：
使用肉桂醛(91.6毫克，0.693毫摩尔)，按照3所述的步骤获得目标化合物15。快速柱色谱(石油醚：乙酸乙酯＝12：1)得到化合物15(181.9毫克，67％，白色固体)。
对化合物15进行检测，其检测结果如下：1H NMR(400MHz,CDCl3)δ7.47(d,J＝7.7Hz,2H),7.39–7.24(m,3H),7.13(d,J＝11.1Hz,1H),6.98–6.72(m,2H),6.18(dd,J＝17.7,11.1Hz,1H),5.43–5.25(m,2H),4.40(d,J＝7.4Hz,1H),3.45(s,1H),2.35(s,2H),2.29–2.17(m,2H),1.96(dd,J＝15.8,7.6Hz,1H),1.78(d,J＝14.5Hz,2H),1.72–1.58(m,3H),1.46(s,3H),1.41–1.31(m,2H),1.15(s,4H),0.99(t,J＝7.3Hz,6H).13C NMR(100MHz,CDCl3)δ205.9,141.0,139.6,136.6,136.2,132.6,129.0,128.9,127.2,124.4,116.0,75.2,66.9,59.9,45.5,45.3,43.7,42.9,37.1,36.4,33.2,32.1,28.7,27.3,18.3,13.8,11. 7.HRMS(ESI):m/z calcd for C29H38NaO3 +[M+Na]+:457.2719；found 457.2722。
(14)化合物16的制备：
化合物16的结构如下：
Figure BDA0003343357760000122
其制备过程如下：
使用间苯氧基苯甲醛(137.4毫克，0.693毫摩尔)，按照3所述的步骤获得目标化合物16。快速柱色谱(石油醚：乙酸乙酯＝12：1)得到化合物16(215.8毫克，69％，白色固体)。
对化合物16进行检测，其检测结果如下：1H NMR(400MHz,CDCl3)δ7.37(t,J＝7.1Hz, 4H),7.21(d,J＝7.7Hz,1H),7.15(t,J＝7.4Hz,1H),7.08(s,1H),7.02(dd,J＝15.2,8.2Hz,3H),6.18 (dd,J＝17.9,11.0Hz,1H),5.39(d,J＝17.6Hz,1H),5.31(d,J＝11.2Hz,1H),4.40(s,1H),3.45(t, J＝6.4Hz,1H),2.44(d,J＝17.0Hz,1H),2.35(d,J＝17.0Hz,1H),2.23(d,J＝11.8Hz,2H),1.96(dd, J＝16.0,7.5Hz,1H),1.72(d,J＝13.5Hz,2H),1.63(t,J＝8.0Hz,2H),1.54(d,J＝6.3Hz,1H),1.47(s, 3H),1.39–1.30(m,2H),1.15(s,3H),1.10–1.03(m,1H),0.99(d,J＝8.5Hz,3H),0.96(d,J＝6.8Hz, 3H).13C NMR(100MHz,CDCl3)δ205.9,157.9,156.5,139.4,137.3,135.7,132.5,130.0,129.9, 125.1,123.9,119.5,119.3,119.2,116.0,75.1,66.8,59.2,45.3,45.1,43.8,42.8,36.9,36.2,35.2, 32.1,28.6,27.2,18.2,13.7,11.6.HRMS(ESI):m/z calcd for C33H40NaO4 +[M+Na]+:523.2824；found 523.2826。
(15)化合物17的制备：
化合物17的结构如下：
Figure BDA0003343357760000131
其制备过程如下：
使用2-吗啉苯甲醛(132.5毫克，0.693毫摩尔)，按照化合物3所述的合成步骤获得目标化合物17。快速柱色谱(石油醚：乙酸乙酯＝12：1)得到化合物17(203.5毫克，66％，白色固体)。
对化合物17进行检测，其检测结果如下：1H NMR(400MHz,CDCl3)δ7.79(s,1H),7.46(d,J＝9.1Hz,1H),7.36–7.31(m,1H),7.09–7.02(m,2H),6.18(dd,J＝17.7,11.1Hz,1H),5.39(dd,J＝17.8,1.4Hz,1H),5.31(dd,J＝11.1,1.3Hz,1H),4.42(d,J＝7.4Hz,1 H),3.98–3.90(m,2H),3.87–3.80(m,2H),3.52(t,J＝5.1Hz,1H),3.00(ddd,J＝11.9,6.3,2.8Hz,2H),2.86(ddd,J＝11.8,6.5,2.7Hz,2H),2.59(dd,J＝16.8,3.3Hz,1H),2.39(dd, J＝16.7,2.0Hz,1H),2.29(d,J＝2.8Hz,1H),2.25(t,J＝6.9Hz,1H),2.00(dd,J＝15.8,7.6Hz,1H),1.71(dq,J＝6.7,3.8Hz,3H),1.67–1.60(m,2H),1.49(s,3H),1.40–1.31(m,2 H),1.26(d,J＝11.4Hz,1H),1.18(s,3H),1.00(d,J＝6.7Hz,3H),0.97(s,3H).13C NMR(100MHz,CDCl3)δ206.0,153.0,139.4,134.2,130.1,130.0,129.5,129.1,122.6,118.6,116.1,75.2,67.2,66.8,59.5,53.1,45.4,45.1,43.9,42.8,36.9,36.2,35.0,31.9,28.5,27. 2,18.2,13.6,11.7.HRMS(ESI):m/z calcd for C31H43NNaO4 +[M+Na]+:516.3090；found5 16.3092。
(16)化合物18的制备：
化合物18的结构如下：
Figure BDA0003343357760000132
其制备过程如下：
使用正丁醛(50.0毫克，0.693毫摩尔)，按照化合物3所述的合成步骤获得目标化合物1 8。快速柱色谱(石油醚：乙酸乙酯＝12：1)获得化合物18(175.4毫克，75％，白色固体)。
对化合物18进行检测，其检测结果如下：1H NMR(400MHz,CDCl3)δ6.59(tt,J＝7.6,2.6 Hz,1H),6.16(dd,J＝17.8,11.1Hz,1H),5.37(dd,J＝17.8,1.4Hz,1H),5.29(dd,J＝11.1,1.4Hz, 1H),4.39(d,J＝7.6Hz,1H),3.41(d,J＝6.4Hz,1H),2.21(d,J＝6.9Hz,1H),2.18(d,J＝2.7Hz,1H), 2.12(dd,J＝9.5,2.4Hz,2H),2.06(t,J＝7.3Hz,2H),1.94(dd,J＝15.8,7.7Hz,1H),1.75–1.69(m, 2H),1.62(d,J＝3.6Hz,2H),1.49(d,J＝2.4Hz,1H),1.46(d,J＝7.4Hz,2H),1.43(s,3H),1.37(t, J＝3.7Hz,1H),1.35–1.32(m,1H),1.25(s,1H),1.14(s,3H),0.98(s,2H),0.96(s,3H),0.94(d,J＝ 2.4Hz,2H),0.91(d,J＝7.4Hz,2H).13C NMR(100MHz,CDCl3)δ205.5,139.6,137.1,136.2, 116.1,75.3,66.9,59.7,45.5,45.2,43.4,42.9,37.1,36.3,32.5,31.8,31.4,28.6,27.3,21.9,18.3, 14.1,13.8,11.7.HRMS(ESI):m/z calcd for C24H38NaO3 +[M+Na]+:397.2719；found 397.2722。
(17)化合物19的制备：
化合物19的结构如下：
Figure BDA0003343357760000141
其制备过程如下：
使用特戊醛(59.7毫克，0.693毫摩尔)，按照化合物3所述的合成步骤获得目标化合物1 9。快速柱色谱(石油醚：乙酸乙酯＝12：1)得到化合物19(184.3毫克，76％，白色固体)。
对化合物19进行检测，其检测结果如下：1H NMR(400MHz,CDCl3)δ6.59(s,1H),6.27–6.08(m,1H),5.44–5.23(m,2H),4.39(d,J＝6.5Hz,1H),3.41(d,J＝6.4Hz,1H),2.31–2.26 (m,1H),2.23–2.18(m,1H),2.10(s,1H),1.92(d,J＝7.3Hz,1H),1.70(s,1H),1.64–1.55(m,4H), 1.44–1.40(m,3H),1.38–1.31(m,2H),1.29–1.22(m,2H),1.16–1.13(m,3H),1.13–1.09(m,6H), 1.06(d,J＝3.6Hz,1H),0.96(td,J＝7.1,3.1Hz,6H),0.92–0.85(m,2H).13C NMR(100MHz, CDCl3)δ206.6,146.7,139.4,132.3,116.1,75.1,66.8,58.3,45.4,45.1,43.1,42.6,36.8,36.1,33.4, 33.2,31.6,29.6,28.5,27.2,18.2,13.6,11.5.HRMS(ESI):m/z calcd for C25H40NaO3 + [M+Na]+:411.2875；found 411.2874。
(18)化合物20的制备：
化合物20的结构如下：
Figure BDA0003343357760000151
其制备过程如下：
使用正戊醛(59.7毫克，0.693毫摩尔)，按照化合物3所述的合成步骤获得目标化合物2 0。快速柱色谱(石油醚：乙酸乙酯＝12：1)得到化合物20(189.2毫克，78％，白色固体)。
对化合物20进行检测，其检测结果如下：1H NMR(400MHz,CDCl3)δ6.58(ddt,J＝7.7,4.9, 2.5Hz,1H),6.16(dd,J＝17.8,11.1Hz,1H),5.37(dd,J＝17.8,1.4Hz,1H),5.30(dd,J＝11.1,1.4Hz, 1H),4.39(dd,J＝7.6,4.8Hz,1H),3.41(t,J＝6.1Hz,1H),2.21(d,J＝7.0Hz,1H),2.18(s,1H), 2.13–2.05(m,2H),1.94(dd,J＝15.8,7.7Hz,1H),1.77–1.64(m,2H),1.61(d,J＝2.1Hz,1H),1.58 (s,1H),1.56–1.42(m,3H),1.43(s,3H),1.43–1.35(m,2H),1.39–1.30(m,2H),1.33–1.25(m,2H), 1.25(s,1H),1.14(s,3H),1.09(dd,J＝14.1,4.5Hz,1H),0.98(s,1H),0.96(s,2H),0.94(s,2H), 0.91(d,J＝1.4Hz,1H),0.88(d,J＝7.2Hz,2H).13C NMR(100MHz,CDCl3)δ205.5,139.5,137.3, 136.0,116.1,75.3,66.9,59.7,45.4,45.2,43.3,42.8,37.0,36.3,32.5,31.8,30.7,29.1,28.6,27.3, 22.7,18.3,14.1,13.8,11.7.HRMS(ESI):m/z calcd for C25H40NaO3 +[M+Na]+:411.2875；found411.2877。
(19)化合物21的制备：
化合物21的结构如下：
Figure BDA0003343357760000152
其制备过程如下：
使用3,3-二甲基丁醛(69.4毫克，0.693毫摩尔)，按照化合物3所述的合成步骤获得目标化合物21。快速柱色谱(石油醚：乙酸乙酯＝12：1)获得化合物21(188.5毫克，75％，白色固体)。
对化合物21进行检测，其检测结果如下：1H NMR(400MHz,CDCl3)δ6.69(tt,J＝8.0,2.6 Hz,1H),6.16(dd,J＝17.8,11.1Hz,1H),5.37(dd,J＝17.8,1.4Hz,1H),5.29(dd,J＝11.1,1.4Hz, 1H),4.38(d,J＝7.6Hz,1H),3.40(d,J＝6.4Hz,1H),2.24–2.17(m,2H),2.13–2.09(m,2H),1.99 (ddd,J＝7.9,5.0,1.5Hz,2H),1.96–1.90(m,1H),1.75–1.67(m,2H),1.62(s,1H),1.58(s,1H),1.48 (dd,J＝13.9,3.7Hz,1H),1.44(s,3H),1.40–1.30(m,2H),1.14(s,3H),1.09–1.04(m,1H),0.98(s, 2H),0.96(d,J＝1.0Hz,3H),0.94(s,1H),0.92(s,9H).13C NMR(100MHz,CDCl3)δ205.3,139.6, 137.4,134.9,116.1,75.3,66.9,59.8,45.5,45.2,43.5,43.4,42.9,37.1,36.3,32.7,32.3,31.8,29.6, 28.6,27.3,18.3,13.8,11.7.HRMS(ESI):m/z calcd for C26H42NaO3 +[M+Na]+:425.3032；found 425.3034。
(20)化合物22的制备：
化合物22的结构如下：
Figure BDA0003343357760000161
其制备过程如下：
使用环己烷基甲醛(77.7毫克，0.693毫摩尔)，按照3所述的步骤获得目标化合物22。快速柱色谱(石油醚：乙酸乙酯＝12：1)获得化合物22(196.7毫克，63％，白色固体)。
对化合物22进行检测，其检测结果如下：1H NMR(400MHz,CDCl3)δ6.42(dt,J＝9.7,2.6Hz,1H),6.16(dd,J＝17.8,11.1Hz,1H),5.37(dd,J＝17.8,1.4Hz,1H),5.29(dd,J ＝11.1,1.4Hz,1H),4.38(d,J＝7.6Hz,1H),3.41(d,J＝6.3Hz,1H),2.21(d,J＝7.2Hz,1 H),2.18–2.14(m,2H),2.12(d,J＝2.1Hz,1H),1.94(dd,J＝15.8,7.7Hz,1H),1.75–1.73 (m,1H),1.72–1.68(m,2H),1.68–1.64(m,2H),1.62(d,J＝3.7Hz,2H),1.58(d,J＝6.3H z,2H),1.50–1.45(m,1H),1.42(s,3H),1.34(dp,J＝13.2,3.3,2.7Hz,2H),1.30–1.24(m, 2H),1.23(s,1H),1.21–1.16(m,2H),1.14(s,3H),1.11(d,J＝4.4Hz,1H),1.06(dd,J＝1 4.1,4.5Hz,1H),0.97(d,J＝4.1Hz,3H),0.95(d,J＝4.1Hz,3H).13C NMR(100MHz,C DCl3)δ206.1,142.0,139.6,134.1,116.1,75.3,66.9,59.6,45.5,45.2,43.4,42.8,38.5,3 7.0,36.3,32.3,31.8,31.8,31.8,28.6,27.3,25.9,25.7,25.6,18.3,13.7,11.7.HRMS(ES I):m/z calcd for C27H42NaO3 +[M+Na]+:437.3032；found 437.3034。
(21)化合物23的制备：
化合物23的结构如下：
Figure BDA0003343357760000162
其制备过程如下：
使用环丙甲醛(48.6毫克，0.693毫摩尔)，按照3所述的步骤获得目标化合物23。快速柱色谱(石油醚：乙酸乙酯＝12：1)获得化合物23(172.1毫克，74％，白色固体)。
对化合物23进行检测，其检测结果如下：1H NMR(400MHz,CDCl3)δ6.17(dd,J＝17.8,11.1Hz,1H),5.98(dt,J＝10.8,2.5Hz,1H),5.38(dd,J＝17.8,1.4Hz,1H),5.30(dd,J＝11.1,1.5Hz,1H),4.40(d,J＝7.6Hz,1H),3.46(d,J＝6.4Hz,1H),2.30(dd,J＝16.1,3.0Hz,1H),2.26–2.23(m,1H),2.21(t,J＝3.5Hz,2H),1.95(dd,J＝15.8,7.7Hz,1H),1.79 –1.74(m,1H),1.68(dd,J＝7.3,4.0Hz,1H),1.63(s,1H),1.59(s,1H),1.53(dd,J＝13.8,3.5Hz,1H),1.47(dt,J＝5.4,2.8Hz,1H),1.43(s,3H),1.41–1.32(m,2H),1.25(s,1H),1.15(s,3H),0.98(d,J＝2.8Hz,3H),0.96(d,J＝2.9Hz,3H),0.95–0.92(m,1H),0.92–0.8 4(m,1H),0.62(ddt,J＝7.0,4.5,2.8Hz,2H).13C NMR(100MHz,CDCl3)δ204.8,142. 3,139.6,133.9,116.0,75.3,67.0,59.4,45.5,45.2,43.5,42.8,37.1,36.4,32.6,31.9,28.7, 27.4,18.3,13.8,12.0,11.7,8.9,8.7.HRMS(ESI):m/z calcd for C24H36NaO3 +[M+Na]+:3 95.2562；found 395.2563。
(22)化合物24的制备：
化合物24的结构如下：
Figure BDA0003343357760000171
其制备过程如下：
使用环戊基甲醛(68.0毫克，0.693毫摩尔)，按照化合物3所述的合成步骤获得目标化合物24。快速柱色谱(石油醚：乙酸乙酯＝12：1)获得化合物24(190.0毫克，76％，白色固体)。
对化合物24进行检测，其检测结果如下：1H NMR(400MHz,CDCl3)δ6.49(d,J＝10.0Hz,1H),6.14(dd,J＝17.8,11.1Hz,1H),5.35(d,J＝17.8Hz,1H),5.27(d,J＝11.1Hz,1H),4.37(d,J＝7.6Hz,1H),3.40(d,J＝6.3Hz,1H),2.52(q,J＝8.4Hz,1H),2.17(d,J＝7.5Hz,2H),2.13(d,J＝13.3Hz,2H),1.92(dd,J＝15.8,7.6Hz,1H),1.79(h,J＝6.5Hz,3H),1.73(s,1H),1.68(q,J＝6.7,5.1Hz,3H),1.60(s,1H),1.57(t,J＝2.8Hz,2H),1.46(dd,J＝13.4,3.7Hz,1H),1.41(s,3H),1.31(td,J＝9.3,7.7,3.8Hz,4H),1.12(s,3H),1.05(dd,J＝14.0,4.4Hz,1H),0.96(s,2H),0.93(d,J＝7.2Hz,4H).13C NMR(100MHz,C DCl3)δ205.8,142.0,139.6,134.4,116.0,75.2,66.9,59.6,45.5,45.2,43.3,42.8,40.1,3 7.0,36.3,33.0,32.8,32.5,31.8,28.6,27.3,25.6,25.6,18.3,13.7,11.6.HRMS(ESI):m/zcalcd for C26H40NaO3 +[M+Na]+:423.2875；found 423.2877。
(23)化合物25的制备：
化合物25的结构如下：
Figure BDA0003343357760000181
其制备过程如下：
使用糠醛(66.6毫克，0.693毫摩尔)，按照化合物3所述的合成步骤获得目标化合物25。快速柱色谱(石油醚：乙酸乙酯＝12：1)获得化合物25(169.1毫克，68％，白色固体)。
对化合物25进行检测，其检测结果如下：1H NMR(400MHz,CDCl3)δ7.52(d,J＝3.7Hz, 1H),7.19(d,J＝2.6Hz,1H),6.61(d,J＝3.8Hz,1H),6.48(d,J＝3.4Hz,1H),6.26–6.10(m,1H), 5.44–5.27(m,2H),4.42(d,J＝8.1Hz,1H),3.47(d,J＝5.4Hz,1H),2.52(q,J＝18.1Hz,2H),2.25(s, 2H),1.96(dd,J＝14.4,9.4Hz,1H),1.78(d,J＝15.2Hz,1H),1.65–1.57(m,3H),1.46(d,J＝2.8Hz, 3H),1.39–1.31(m,2H),1.29–1.23(m,2H),1.14(d,J＝3.8Hz,3H),1.02(td,J＝4.8,2.4Hz,3H), 0.98(d,J＝3.2Hz,3H).13C NMR(100MHz,CDCl3)δ206.0,152.4,144.8,139.6,132.9,119.8, 116.1,115.5,112.5,75.4,67.0,59.5,45.5,45.3,43.7,42.9,37.1,36.4,35.1,32.5,28.7,27.4,18.3, 13.8,11.8.HRMS(ESI):m/zcalcd for C25H34NaO4 +[M+Na]+:421.2355；found 421.2356。
(24)化合物26的制备：
化合物26的结构如下：
Figure BDA0003343357760000182
其制备过程如下：
使用3-吡啶甲醛(74.2毫克，0.693毫摩尔)，按照化合物3所述的合成步骤获得目标化合物26。快速柱色谱(石油醚：乙酸乙酯＝12：1)获得化合物26(171.3毫克，67％，白色固体)。
对化合物26进行检测，其检测结果如下：1H NMR(400MHz,CDCl3)δ8.75(s,1H),8.56 (d,J＝4.4Hz,1H),7.78(d,J＝8.0Hz,1H),7.39(s,1H),7.34(dd,J＝8.0,4.8Hz,1H),6.18(dd, J＝17.8,11.1Hz,1H),5.37(s,1H),5.32(d,J＝11.1Hz,1H),4.42(d,J＝7.6Hz,1H),3.49(d,J＝6.3 Hz,1H),2.58(dd,J＝17.0,3.3Hz,1H),2.44(dd,J＝17.0,2.1Hz,1H),2.31–2.21(m,2H),1.98(dd, J＝15.9,7.6Hz,1H),1.76(dt,J＝14.6,3.4Hz,2H),1.70(dd,J＝7.3,4.0Hz,1H),1.65(d,J＝15.9Hz, 2H),1.48(s,3H),1.37(dt,J＝17.7,4.4Hz,2H),1.17(s,3H),1.07(dd,J＝14.2,4.4Hz,1H),1.01(d, J＝6.3Hz,3H),0.99(s,3H).13C NMR(100MHz,CDCl3)δ205.6,151.0,149.5,139.5,137.6, 136.9,131.7,129.2,123.8,116.0,75.2,66.8,59.5,45.5,45.3,44.0,42.9,37.0,36.3,35.3,32.3, 28.7,27.2,18.2,13.8,11.7.HRMS(ESI):m/z calcd for C26H35NNaO3 +[M+Na]+:432.2515；found 432.2516。
(25)化合物27的制备：
化合物27的结构如下：
Figure BDA0003343357760000191
其制备过程如下：
使用乙醛酸(51.3毫克，0.693毫摩尔)，按照化合物3所述的合成步骤获得目标化合物2 7。快速柱色谱(石油醚：乙酸乙酯＝12：1)获得化合物27(152.7毫克，65％，白色固体)。对化合物27进行检测，其检测结果如下：1H NMR(400MHz,CDCl3)δ7.59(s,1H),6.16(dd, J＝17.8,11.1Hz,1H),5.40–5.25(m,2H),4.34(d,J＝8.0Hz,1H),3.22(d,J＝1.2Hz,2H), 3.08(d,J＝7.0Hz,1H),2.29(s,1H),2.22(dd,J＝14.3,2.7Hz,1H),2.12(t,J＝7.1Hz,1 H),2.02(dd,J＝16.0,8.0Hz,1H),1.65(d,J＝15.9Hz,2H),1.55(d,J＝3.4Hz,1H),1.52 (d,J＝3.5Hz,1H),1.45(s,3H),1.38(dd,J＝13.9,3.6Hz,1H),1.25(s,1H),1.15–1.08 (m,6H),1.02(d,J＝6.8Hz,3H),0.95(dd,J＝13.7,4.3Hz,1H).13C NMR(101MHz,CD Cl3)δ207.5,162.0,139.4,136.7,116.3,84.9,76.3,67.2,60.0,50.0,46.0,45.8,43.0,39. 0,38.5,35.9,31.2,28.6,27.3,17.8,13.3,12.1.HRMS(ESI):m/z calcdfor C31H40NaO5 + [M+Na]+:515.2768；found 515.2772。
效果验证例：
抗细胞增殖试验。采用CCK-8法评价不同细胞株的药物敏感性。将细胞以(8.0-10.0) ×103细胞/孔的方式接种于96孔板，最终体积为90μL，然后加入10μL不同浓度的化合物。置于37℃，5％CO2培养箱孵育72h后，每孔加入10μL CCK-8(Vazyme,A311-01)溶液，继续孵育3-4h。用THERMO FISHER Multiskan FC在450nm处读取OD值。用GraphPa d Prizm7计算抑制50％生长所需的浓度(IC50)。其结果如表1所示，其中，+代表IC50在10 -1uM，++代表IC50在1-0.1uM，+++代表IC50在0.1-0.01uM，++++代表IC50<0.01uM。
表1
Figure BDA0003343357760000201

Claims (8)

1.一种二萜衍生物，其特征在于，其结构如式Ⅰ所示：
Figure FDA0003343357750000011
所述R1为苯基、链状脂肪烃、环状脂肪烃或含杂原子芳香环。
2.根据权利要求1所述的二萜衍生物，其特征在于，R1的结构为化合物3-27中的一种：
Figure FDA0003343357750000012
Figure FDA0003343357750000021
3.一种二萜衍生物的制备方法，其特征在于，其制备路线如下所示：
Figure FDA0003343357750000022
4.权利要求1或2所述的二萜衍生物在制备治疗癌症、预防癌症和/或改善癌症症状的药物或食品中的应用。
5.根据权利要求4所述的应用，其特征在于，所述癌症包括妇科癌、内分泌癌、骨癌、肺癌、脑和CNS肿瘤、胃肠癌、泌尿生殖器癌、头和颈部肿瘤、血癌、骨髓癌血液病症、淋巴癌、眼癌、皮肤癌、软组织肉瘤。
6.根据权利要求5所述的应用，其特征在于，所述癌症包括乳腺癌、结直肠癌、肺癌。
7.一种药物组合物，其特征在于，其活性成分为权利要求1或2所述的二萜衍生物。
8.根据权利要求7所述的药物组合物，其特征在于，还包括溶剂或可药用载体。
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